Micelles formed by diblock copolymers with critical micelle concentration (Cmc) character have been widely investigated for biomedical applications. For anticancer drug delivery, micelles could be roughly divided into two categories based on the drug loading forms. The first category is that micelles consist of polymer-drug conjugates. This kind of micelles guesses more stabile in circulation because almost anticancer drugs are insoluble. The other category is micelles encapsulated drug by physically hydrophobic interaction. However, some of this type of micelles cannot maintain their integral structures due to dramatic dilution after intravenous injection [1]. Several strategies were proposed to overcome such stability problem. For example, micellar structure was strengthen by crosslinking the core and/or shell regions [2,3] and by mixing a crystalline copolymer and a copolymer with lower Cmc to prevent any copolymer dissociation from micelles [4-6].
A portion of Cmc diblock copolymers that with conspicuous temperature-sensitive character, especially for lower critical concentration temperature (LCST) have attracted significant interest continually because of their phase-transition properties, self-assembling to well-established core-shell micelle structure, and wide-ranging applications [7-11]. However, the studies of temperature-sensitive copolymers for drug delivery in vivo are limited, only in the areas of intramuscular or intraperitoneal injection [12,13]. Several critical issues prohibited their broad uses in drug delivery under micelle type. The major problem of temperature-sensitive diblock copolymers is biocompatibility. Most of the temperature-sensitive copolymers are not approved in vivo used. Second, drug release mechanism from temperature-sensitive diblock copolymer-forming micelles is difficult to control due to their phase-transition temperature. Furthermore, poor micellar stability causes serious drug safety issue in clinical application. The above-mentioned problems hinder temperature-sensitive diblock copolymer-forming micelles from gaining significant progress in biomedical applications, especially in intracellular drug delivery.
US patent publication No. 2008/081075 A1 discloses a mixed micelle structure with a functional inner core and hydrophilic outer shell self-assembled from a graft macromolecule and one or more block copolymer, and preferably from a graft copolymer and two or more diblock copolymers. Said graft macromolecule comprising a backbone and hydrophobic side chains bound to the backbone, said block copolymer comprising a hydrophobic polymeric segment and a hydrophilic polymeric segment, wherein the hydrophobic side chains of said graft macromolecule are aggregated, and the hydrophobic polymeric segment of said block polymer is packed and associated to the aggregated hydrophobic side chains of the graft macromolecule with the hydrophilic polymeric segment of the block polymer extruding therefrom to form the core-shell structure. This mixed micelle forms a micellar solution in an aqueous medium, which is temperature sensitive and pH sensitive. Preferably, a terminal functionality is connected to an end of the hydrophilic polymeric segment of said block copolymer, and said terminal functionality is a ligand able to be bound to a receptor on a surface of a tumor cell, a fluorescence group or a dye, so that the mixed micelle is suitable for use as a cancer diagnosis agent and a cancer hydrophobic drug delivery carrier. The disclosure of US patent publication No. 2008/081075 A1 is incorporated herein by reference.